The kinetic disposition of morphine and its metabolites in rats is being investigated. Kinetic models are constructed which include pharmacokinetics and kinetics of in vivo "opiate receptor" binding. Such a model, if providing a unique and accurate solution, is capable of predicting receptor occupancy following morphine administration and can be correlated to the time course of pharmacological events such as dependence and withdrawal in addicted rats. Disposition kinetics will be studied in naive and addicted rats with and without coadministration of opiate antagonists to prevent "opiate receptor" binding. Stable isotope dilution - mass fragmentography is the primary analytical tool, since extreme sensitivity and specificity are required. Tritium and C14-labeled morphine are concurrently used to account for all metabolites. Further opiate agonists and antagonists will be included with this study at a later time to substantiate the kinetic model. Also kinetics of brain biogenic amines can be studied in the future as correlates to the kinetic disposition of morphine. Detailed knowledge of kinetic events following opiate administration is essential for an understanding of pharmacological response, development of tolerance, addiction and withdrawal.